We have developed a rat model in which chronic daily ethanol consumption/daily withdrawal induces hypothalamo-pituitary-adrenal (HPA), brain proopiomelanocortin (POMC) opioid, behavioral (e.g., anxiety), sympathoadrenal and metabolic changes persisting long (at least 4 weeks) after stopping ethanol consumption. These changes are functionally interdependent and have each been individually suggested to contribute to alcoholism. Furthermore, this overall HPA+POMC+sympathoadrenal+metabolic+behavioral (HPSMB) 'syndrome' is consistent with characteristics exhibited by abstinent alcoholics, ethanol-preferring rat strains, non-alcoholic individuals with familial propensity to alcoholism, and post-traumatic stress disorder (PTSD) patients highly prone to ethanol abuse. The long-lasting post-ethanol changes in these interdependent functions thus likely play important roles in ethanol dependence and/or relapse. Specific Aim 1 is to determine the time course and identify potential mechanisms for the HPSMB syndrome, using our well-characterized and reproducible daily ethanol consumption/withdrawal model. These investigations will include evaluating diurnal changes, duration, and delayed expression of responses. Specific Aim 2 is to determine whether investigator-administered versus elective ethanol self-administration alters induction of the HPSMB syndrome. Specific Aim 3 is assess the likely role of the HPSMB syndrome in producing the alcohol deprivation effect. To achieve these aims, changes associated with the HPSMB syndrome will be assessed as behavioral (anxiety), endocrine, in vitro, and brain and pituitary gene expression responses characteristic of, consistent with, or contributing to alcohol abuse and relapse.